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PubMed2001

Clinical and genetic distinction between Walker-Warburg syndrome and muscle-eye-brain disease.

BACKGROUND: Three rare autosomal recessive disorders share the combination of congenital muscular dystrophy and brain malformations including a neuronal migration defect: muscle-eye-brain disease (MEB), Walker-Warburg syndrome (WWS), and Fukuyama congenital muscular dystrophy (FCMD). In addition, ocular abnormalities are a constant feature in MEB and WWS. Lack of consistent ocular abnormalities in FCMD has allowed a clear clinical demarcation of this syndrome, whereas the phenotypic distinction between MEB and WWS has remained controversial. The MEB gene is located on chromosome 1p32-p34. OBJECTIVES: To establish distinguishing diagnostic criteria for MEB and WWS and to determine whether MEB and WWS are allelic disorders. METHODS: The authors undertook clinical characterization followed by linkage analysis in 19 MEB/WWS families with 29 affected individuals. With use of clinical diagnostic criteria based on Finnish patients with MEB, each patient was categorized as having either MEB or WWS. A linkage and haplotype analysis using 10 markers spanning the MEB locus was performed on the entire family resource. RESULTS: Patients in 11 families were classified as having MEB and in 8 families as WWS. Strong evidence in favor of genetic heterogeneity was obtained in the 19 families. There was evidence for linkage to 1p32-p34 in all but 1 of the 11 pedigrees segregating the MEB phenotype. In contrast, linkage to the MEB locus was excluded in seven of eight of the WWS families. CONCLUSION: These results allow the classification of MEB and WWS as distinct disorders on both clinical and genetic grounds and provide a basis for the mapping of the WWS gene(s).

Adolescent↗
PubMed1994

Expression of the complement membrane attack complex and its inhibitors in Pick disease brain.

The immunohistochemical localization of the complement membrane attack complex (MAC) was examined in Pick disease brain and compared with the distribution of three of its inhibitors, vitronectin, protectin and clusterin. Pick bodies were stained intensely for both the MAC and protectin, weakly for vitronectin, but negatively for clusterin. However, the clusterin antibody intensely stained some pyramidal neurons in affected cortical areas, including ballooned neurons. The present study indicates that a complement-mediated attack is associated with the formation of Pick bodies, and provides further suggestive evidence that clusterin may be a marker for active neuronal degeneration.

Aged↗
PubMed1978

Stereopsis and unilateral brain disease.

Performance on a random-letter stereoscopic task has been reported to be affected by right but not left cerebral disease. Subsequent studies employing a conventional stereoacuity test have challenged these results and proposed that dementia may be the primary determinant of impaired stereopsis in the patients with brain disease. The latter investigators have failed to distinguish between local and global stereopsis. The present study confirms the original findings, rules out dementia as a potential artifact, and attempts to reconcile the conflicting series of reports.

Adolescent↗
PubMed1984

Propranolol in the treatment of assaultive patients with organic brain disease.

Propranolol in doses up to 520 mg/day was administered to eight patients with organic brain disease characterized by violent and assaultive behavior refractory to conventional treatment. Improvement was demonstrated in the seven patients able to tolerate adequate drug dosages. Hypotension, bradycardia, and interactions with other medications constituted complications.

Adult↗
PubMed1998

Altropane, a SPECT or PET imaging probe for dopamine neurons: III. Human dopamine transporter in postmortem normal and Parkinson's diseased brain.

Increasing evidence suggests that the dopamine transporter is situated almost exclusively on dopamine neurons. Accordingly, it is an valuable marker for Parkinson's disease and other pathological states of dopamine neurons. We previously demonstrated that the potent dopamine transport inhibitor [125I]altropane (IACFT:E-N-iodoallyl-2beta-carbomethoxy-3beta-(4-fluor ophenyl)tropane) is a high affinity selective probe for the dopamine transporter in monkey brain and an effective SPECT imaging agent in nonhuman primate brain. We now report the binding properties of [125I]altropane in postmortem tissue of normal human brain and compare the findings to Parkinson's diseased brain. In homogenates of human brain putamen, [125I]altropane bound with high affinity (KD: 4.96 +/- 0.38 nM, n = 4) and site density (BMAX: 212 +/- 41.1 pmol/g original wet tissue weight) well within the density range reported previously for the dopamine transporter in this brain region. Drugs inhibited [125I]altropane binding with a rank order of potency that corresponded closely to their rank order for blocking dopamine transport (r 0.98, P < 0.001). In postmortem Parkinson's diseased brain, bound [125I]altropane (1 nM) was markedly reduced (89%, 99% in putamen, depending on measures of nonspecific binding) compared with normal aged-matched controls (normal putamen: 49.2 +/- 8.1 pmol/g; Parkinson's diseased putamen: 0.48 +/- 0.33 pmol/g; n = 4). In vitro autoradiography, conducted in tissue sections at a single plane of the basal ganglia, revealed high levels of [125I]altropane binding the caudate nucleus and putamen, but lower levels (73% of the caudate-putamen) in the nucleus accumbens (n = 7). In Parkinson's diseased brains (n = 4), [125I]altropane binding was 13% of the levels detected in normal putamen, 17% of normal values in the caudate nucleus, and 25% of normal levels in nucleus accumbens. The association of [125I]altropane to the dopamine transporter in human postmortem tissue, the marked reduction of [125I]altropane binding in Parkinson's diseased brains, its rapid entry into brain and highly localized distribution in dopamine-rich brain regions, support its use as a probe for monitoring the dopamine transporter in vitro and in vivo by SPECT imaging.

Aged↗
PubMed1997

Mercury vapor inhalation inhibits binding of GTP to tubulin in rat brain: similarity to a molecular lesion in Alzheimer diseased brain.

Hg2+ interacts with brain tubulin and disassembles microtubules that maintain neurite structure. Since it is well known that Hg vapor (Hg0) is continuously released from "silver" amalgam tooth fillings and is absorbed into brain, rats were exposed to Hg0 4h/day for 0, 2, 7, 14 and 28 d at 250 or 300 micrograms Hg/m3 air, concentrations present in mouth air of some humans with many amalgam fillings. Average rat brain Hg concentrations increased significantly (11-47 fold) with duration of Hg0 exposure. By 14 d Hg0 exposure, photoaffinity labelling on the beta-subunit of the tubulin dimer with [alpha 32P] 8N3 GTP in brain homogenates was decreased 41-74%, upon analysis of SDS-PAGE autoradiograms. The identical neurochemical lesion of similar or greater magnitude is evident in Alzheimer brain homogenates from approximately 80% of patients, when compared to human age-matched neurological controls. Total tubulin protein levels remained relatively unchanged between Hg0 exposed rat brains and controls, and between Alzheimer brains and controls. Since the rate of tubulin polymerization is dependent upon binding of GTP to tubulin dimers, we conclude that chronic inhalation of low-level Hg0 can inhibit polymerization of brain tubulin essential for formation of microtubules.

Administration, Inhalation↗
PubMed1990

Neuroleptic malignant syndrome in organic brain disease and physical illness.

The neuroleptic malignant syndrome is a serious complication associated with the use of antipsychotic drugs that has received a great deal of interest in recent times. Although its aetiology has not been fully understood, it often occurs in association with underlying brain disease and physical debilitation. Two such cases are described. The various hypotheses concerning the aetiology and pathogenesis of this condition are also discussed.

Adult↗
PubMed2002

Estrogen replacement therapy is associated with less progression of subclinical structural brain disease in normal elderly women: a pilot study.

BACKGROUND: Cortical atrophy, central atrophy, deep white-matter hyperintensities, and periventricular hyperintensities are reported in normal aging. OBJECTIVES: We examined the effects of estrogen replacement therapy (ERT) on these forms of 'subclinical structural brain disease' (SSBD) in normal, postmenopausal women in a pilot, naturalistic, longitudinal study of 15 subjects. METHODS: Two assessments were performed at least two years apart, with volumetric magnetic resonance imaging (MRI) and neuropsychological testing. RESULTS: Women receiving open-label ERT showed significantly less progression of SSBD than those who did not. CONCLUSIONS: The association between reduced SSBD progression and ERT suggests this intervention could help preserve normal brain structure in healthy elderly women.

Aged↗
PubMed2003

Proteomic analysis of oxidatively modified proteins in Alzheimer's disease brain: insights into neurodegeneration.

Identification of oxidized proteins in Alzheimer's disease (AD) brain is hypothesized to lead to new insights into mechanisms of neurodegeneration and synapse loss in this dementing disorder that are associated with oxidative stress. Previous studies had shown increased oxidation of proteins in AD brain, but identifying those particular proteins that were specifically oxidized using standard immunochemical methods is a daunting task when one considers how many proteins there are in brain. To address this issue, proteomics has been used to identify specifically modified proteins in AD brain. This review outlines the nature of proteomics, the proteins identified in AD brain that are specifically oxidatively modified, and provides rational consequences related to neurodegeneration and synapse loss as sequelae to loss of function, due to oxidation and consistent with the known pathological and biochemical alteration in AD brain. The use of proteomics to learn about disease mechanisms is still embryonic, but the emerging techniques of proteomics represent a promising means to elucidate mechanisms of disease at the protein level. There are limitations to proteomics, and these, too, are discussed.

Alzheimer Disease↗
PubMed1995

Gene expression and cellular content of cathepsin D in Alzheimer's disease brain: evidence for early up-regulation of the endosomal-lysosomal system.

In Alzheimer's disease brains, more than 90% of pyramidal neurons in lamina V and 70% in lamina III displayed 2- to 5-fold elevated levels of cathepsin D (Cat D) mRNA by in situ hybridization compared with neurologically normal controls. Most of these cells appeared histologically normal. The less vulnerable nonpyramidal neuron population in lamina IV had relatively normal message levels. Neuronal populations expressing more Cat D mRNA also displayed quantitatively increased Cat D immunoreactive protein. Cat D mRNA expression was only moderately increased in astrocytes. Degenerating neurons exhibited intense immunoreactivity but lowered Cat D mRNA levels. The upregulation of Cat D synthesis and accumulation of hydrolase-laden lysosomes indicate an early activation of the endosomal-lysosomal system in vulnerable neuronal populations, possibly reflecting early regenerative or repair processes. These abnormalities also represent a basis for altered regulation of amyloid precursor protein processing.

Aged↗
PubMed1985

[Social-vocational adaptation of patients with neurosis-like forms of organic brain disease].

Using a number of indices the authors studied a long-term follow-up of 70 patients with neurosis-like forms of organic diseases affecting the brain (arachnoidites, encephalitides, diencephalitides). The time-course was assessed by clinical improvement and improvement in social functioning. Three groups of patients were specified, who were characterized by a definite type of personal response to the disease and peculiarities of social and occupational adaptation. The distribution of patients by groups and, hence, the clinical, social and occupational prognosis are determined by the psychoneurotic component of the disease rather than by the organic one.

Adult↗
PubMed2006

Alpha1-antichymotrypsin, an inflammatory protein overexpressed in Alzheimer's disease brain, induces tau phosphorylation in neurons.

Amyloid plaques and neurofibrillary tangles are key pathological features of Alzheimer's disease. Alzheimer's disease pathology is also characterized by neuroinflammation and neuronal degeneration, with the proteins associated with inflammatory responses being found in tight association with the plaques. One such protein is the serine protease inhibitor alpha-1-antichymotrypsin (ACT). ACT has been shown to promote Abeta polymerization in vitro and in vivo, and levels of ACT protein in plasma and cerebrospinal fluid from Alzheimer's patients have been found to correlate with progression of dementia. Here we investigated the possible involvement of ACT in tau phosphorylation and tangle formation. As was previously found for Alzheimer's disease, brains from patients with non-Alzheimer's tauopathies exhibited an enhanced expression of ACT, which correlated with the level of tau hyperphosphorylation. Transgenic mice expressing human ACT alone or ACT along with mutant human amyloid precursor protein (APP) showed a significant increase in tau phosphorylation, suggesting that this inflammatory protein can induce tau hyperphosphorylation. The increase in phosphorylation was observed at PHF-1 (P-Ser396/P-Thr404), P-Ser202 and P-Thr231 sites on tau, the P-tau epitopes that are associated with tangles in the patients. This result was further confirmed by the finding that addition of purified ACT induced the same Alzheimer's disease-related tau hyperphosphorylation in cortical neurons cultured in vitro. This correlated with an increase in extracellular signal regulated kinase (ERK) and glycogen synthase kinase-3 activation, indicating their involvement in ACT-induced tau phosphorylation. The ACT-treated neurons showed neurite loss and subsequently underwent apoptosis. Approximately 40-50% of neurons were TUNEL positive by 6 and at 24 h >70% of the neurons showed staining suggesting that ACT was inducing apoptosis in these neurons. These findings indicate that inappropriate inflammatory responses are a potential threat to the brain and that intervention directed at inhibiting the expression or function of ACT could be of therapeutic value in neurodegenerative diseases such as Alzheimer's and other tauopathies.

Alzheimer Disease↗
PubMed2000

Brain-derived neurotrophic factor and neurotrophin-3 levels in Alzheimer's disease brains.

In the present study, we investigated the levels of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) in post-mortem brain tissue of Alzheimer's disease (AD) patients, and we observed a significant increase of BDNF concentration in hippocampus and parietal cortex of AD patients, as well as a negative correlation between NT-3 levels and age in hippocampus and putamen of control subjects, and for BDNF in frontal cortex. A defining feature of AD is the post-mortem identification of neuritic plaques and neurofibrillary tangles in the brain, however, a more significant neuropathological finding is the degeneration of cholinergic neurones of the basal forebrain, critically involved in memory and cognition. Neurotrophic factors are partly responsible for the maintenance of neuronal function and structural integrity in the adult brain. Our results provide, therefore, evidence that, under conditions of progressive neurodegeneration the brain stimulates the over expression of certain neurotrophic factors as a possible mechanisms of compensation, and that during senescence the expression of these molecules is regulated.

Age Factors↗
PubMed1991

Mitral valve prolapse in young Israelis with thromboembolic brain disease.

In order to establish the association between mitral valve prolapse (MVP) and the incidence of thromboembolic disease of the brain we reassessed 36 patients (less than or equal to 50 years old) who were hospitalized during 1983-85 because of cerebrovascular accidents. The patients underwent complete physical and neurological examinations, blood tests including coagulogram and two-dimensional echocardiogram. The control group comprised 117 patients without cerebrovascular events. In the study group, 4 patients (11.1%) had MVP compared with 10 (8.5%) in the control group. Of these four, only one male did not have any risk factor for thromboembolic event; among the other three the risk factors were systemic lupus erythematosus, hyperlipidemia, diabetes, hypertension and pregnancy. We conclude that our results are in accordance with most of the literature that MVP is not a risk factor for thromboembolic disease except in Greek and Italian populations, which are ethnically more homogeneous than other Western societies studied.

Adult↗
PubMed1991

Abnormal tau proteins from Alzheimer's disease brains. Purification and amino acid analysis.

Abnormal tau proteins (PHF-tau) were isolated from Alzheimer's disease brains by treatment of paired helical filament enriched-fractions with perchloric acid and boiling of the acid precipitable fraction with beta-mercaptoethanol. These proteins were purified further by a second perchloric acid treatment. The purified PHF-tau proteins were soluble in buffers devoid of sodium dodecyl sulfate. However, they were similar to the abnormal tau extracted from paired helical filaments with sodium dodecyl sulfate, also named A68, in molecular mass (68, 64, and 60 kDa), isoelectric point (pI 5.5-6.5), reactivity with anti-tau antibodies, and in requirement for alkaline phosphatase treatment to bind the Tau-1 antibody. Compared to normal tau, the soluble PHF-tau contained 100% more glycine and 35% less lysine residue. The results suggest that besides phosphorylation other types of modification may be involved in differentiating PHF-tau from normal tau.

Alzheimer Disease↗